Publikationsdatum:
2010-07-03
Beschreibung:
Generally, F-box proteins are the substrate recognition subunits of SCF (Skp1-Cul1-F-box protein) ubiquitin ligase complexes, which mediate the timely proteolysis of important eukaryotic regulatory proteins. Mammalian genomes encode roughly 70 F-box proteins, but only a handful have established functions. The F-box protein family obtained its name from Cyclin F (also called Fbxo1), in which the F-box motif (the approximately 40-amino-acid domain required for binding to Skp1) was first described. Cyclin F, which is encoded by an essential gene, also contains a cyclin box domain, but in contrast to most cyclins, it does not bind or activate any cyclin-dependent kinases (CDKs). However, like other cyclins, Cyclin F oscillates during the cell cycle, with protein levels peaking in G2. Despite its essential nature and status as the founding member of the F-box protein family, Cyclin F remains an orphan protein, whose functions are unknown. Starting from an unbiased screen, we identified CP110, a protein that is essential for centrosome duplication, as an interactor and substrate of Cyclin F. Using a mode of substrate binding distinct from other F-box protein-substrate pairs, CP110 and Cyclin F physically associate on the centrioles during the G2 phase of the cell cycle, and CP110 is ubiquitylated by the SCF(Cyclin F) ubiquitin ligase complex, leading to its degradation. siRNA-mediated depletion of Cyclin F in G2 induces centrosomal and mitotic abnormalities, such as multipolar spindles and asymmetric, bipolar spindles with lagging chromosomes. These phenotypes were reverted by co-silencing CP110 and were recapitulated by expressing a stable mutant of CP110 that cannot bind Cyclin F. Finally, expression of a stable CP110 mutant in cultured cells also promotes the formation of micronuclei, a hallmark of chromosome instability. We propose that SCF(Cyclin F)-mediated degradation of CP110 is required for the fidelity of mitosis and genome integrity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946399/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946399/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉D'Angiolella, Vincenzo -- Donato, Valerio -- Vijayakumar, Sangeetha -- Saraf, Anita -- Florens, Laurence -- Washburn, Michael P -- Dynlacht, Brian -- Pagano, Michele -- R01 GM057587/GM/NIGMS NIH HHS/ -- R01 GM057587-12/GM/NIGMS NIH HHS/ -- R01-GM057587/GM/NIGMS NIH HHS/ -- R21 AG032560/AG/NIA NIH HHS/ -- R21 AG032560-02/AG/NIA NIH HHS/ -- R21-AG032560/AG/NIA NIH HHS/ -- R37 CA076584/CA/NCI NIH HHS/ -- R37 CA076584-12/CA/NCI NIH HHS/ -- R37-CA076584/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Jul 1;466(7302):138-42. doi: 10.1038/nature09140.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20596027" target="_blank"〉PubMed〈/a〉
Schlagwort(e):
Animals
;
Cell Cycle Proteins/*metabolism
;
Cell Line
;
Cell Line, Tumor
;
Centrioles/metabolism
;
Centrosome/chemistry/*metabolism
;
Cyclins/chemistry/deficiency/genetics/*metabolism
;
G2 Phase
;
*Homeostasis
;
Humans
;
Mice
;
Microtubule-Associated Proteins/*metabolism
;
*Mitosis
;
Multiprotein Complexes/metabolism
;
Phenotype
;
Phosphoproteins/*metabolism
;
Protein Binding
;
SKP Cullin F-Box Protein Ligases/metabolism
;
Substrate Specificity
;
Ubiquitination
Print ISSN:
0028-0836
Digitale ISSN:
1476-4687
Thema:
Biologie
,
Chemie und Pharmazie
,
Medizin
,
Allgemeine Naturwissenschaft
,
Physik
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